EP2791134A1 - Composé chimique utile en tant qu'intermédiaire pour la préparation d'un inhibiteur de catéchol-o-méthyltransférase - Google Patents

Composé chimique utile en tant qu'intermédiaire pour la préparation d'un inhibiteur de catéchol-o-méthyltransférase

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Publication number
EP2791134A1
EP2791134A1 EP12806720.4A EP12806720A EP2791134A1 EP 2791134 A1 EP2791134 A1 EP 2791134A1 EP 12806720 A EP12806720 A EP 12806720A EP 2791134 A1 EP2791134 A1 EP 2791134A1
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EP
European Patent Office
Prior art keywords
formula
compound
reaction
mixture
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
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EP12806720.4A
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German (de)
English (en)
Other versions
EP2791134B1 (fr
Inventor
Domenico Russo
Laszlo Erno Kiss
Jorge Bruno Reis Wahnon
David Alexander Learmonth
Tibor Eszenyi
Axel Zimmermann
Bjoern Schlummer
Michael Kreis
Klaus Reiter
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Bial Portela and Cia SA
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Bial Portela and Cia SA
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Priority claimed from GBGB1121413.7A external-priority patent/GB201121413D0/en
Priority claimed from GBGB1201758.8A external-priority patent/GB201201758D0/en
Priority to EP19194756.3A priority Critical patent/EP3604299B1/fr
Application filed by Bial Portela and Cia SA filed Critical Bial Portela and Cia SA
Priority to RS20191562A priority patent/RS59666B1/sr
Priority to SI201231703T priority patent/SI2791134T1/sl
Priority to PL12806720T priority patent/PL2791134T3/pl
Publication of EP2791134A1 publication Critical patent/EP2791134A1/fr
Publication of EP2791134B1 publication Critical patent/EP2791134B1/fr
Application granted granted Critical
Priority to HRP20192133TT priority patent/HRP20192133T8/hr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel compound and to processes which employ it in the preparation of a catechol-O-methyltransferase inhibitor.
  • this invention relates to 5-[3-(2,5-dichloro-4,6-dimethyl-l-oxy-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-2- hydroxy-3-methoxy-l -nitrobenzene which can be used in the process for the preparation of 5-[3-(2,5-dichloro-4,6-dimethyl-l-oxy-pyridin-3-yl)-[l,2,4]oxadiazoI-5-yl]-3- nitrobenzene- 1 ,2-diol .
  • a preferred method of treatment of Parkinson's disease is the administration of a combination of levodopa and a peripherally selective aromatic amino acid decarboxylase inhibitor (AADCI) together with a catechol-O-methyltransferase (COMT) inhibitor.
  • AADCI peripherally selective aromatic amino acid decarboxylase inhibitor
  • COMP catechol-O-methyltransferase
  • the currently employed COMT inhibitors are tolcapone and entacapone.
  • some authorities believe that each of these COMT inhibitors have residual problems relating to pharmacokinetic or pharmacodynamic properties, or to clinical efficiency or safety. Hence, not all patients get most benefit from their levodopa/ AADCI/COMT inhibitor therapy.
  • Dl, D2 and D3 also disclosed methods of preparing the new COMT inhibitors.
  • Other benefits which would be appropriate include those selected from reduction in number of process steps, reduction in number of unit operations, reduction of cycle-times, increased space yield, increased safety, easier to handle reagents/reactants and/or increase in purity of the COMT inhibitor, especially when manufacture of larger quantities are envisaged.
  • a process has now been discovered that proceeds via a new intermediate which is suitable for manufacture of commercially useful quantities of a particularly apt COMT inhibitor in good yield. Additional benefits occur such as those selected from a reduced number of process steps and number of unit operations, reduced cycle-times, increased space yield, increased safety, with easier to handle reagents/reactants, improved impurity profile and/or good purity.
  • the present invention in one aspect provides 5-[3-(2,5-dichloro-4,6-dimethyl-l-oxy- pyridin-3-yl)-[l ,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-l-nitrobenzene and salts thereof, that is the compound of the formula (I):
  • the compound of formula (I) is unsalted.
  • salts of the hydroxy group with metal ions such as the alkali or alkaline earth metals, particularly the sodium and potassium salts are provided as well as those of highly basic organic compounds such as guanidine or the like.
  • the compound of formula (I) or its salt is provided in a form suitable for use as a chemical intermediate.
  • This may be, for example, in a form at least 50% pure, in crystalline form, in solid form or in an organic solvent or the like.
  • the compound of formula (I) is useful as an intermediate in the preparation of 5-[3-(2,5- dichloro-4 , 6-dimethyl- 1 -oxy-pyridin-3-yl)-[ 1 ,2,4] oxadiazol-5-yl] -3-nitrobenzene- 1 , 2-diol i.e. the compound of formula II):
  • the compound of formula (II) may also be referred to as opicapone or 2,5-dichloro-3-(5- (3,4-dihydroxy-5-nitrophenyl)-[l,2,4]-oxadiazole-3-yl)-4,6-dimethylpyridine-l-oxide.
  • Opicapone has been found to be more potent than tolcapone in inhibiting liver COMT both at 3 hours and 6 hours post oral administration to rats [ED50 in mg/kg, opicapone 0.87 at 3 hours and 1.12 at 6 hours as compared to tolcapone 1.28 at 3 hours and 2.08 at 6 hours].
  • Opicapone at a dose of 3 mg/kg was found to be more effective at inhibiting rat liver COMT with nearly complete inhibition occurring 2 to 6 hours post oral administration with only about 90% of enzyme activity recovered after 72 hours while tolcapone provided shorter duration of activity with about 84% recovery after only 9 hours.
  • Both opicapone and tolcapone inhibit human recombinant S-COMT but opicapone has an inhibitory constant of 16pM being 10 fold lower than that for tolcapone.
  • opicapone following oral administration to the rat was found to be devoid of effect whereas tolcapone inhibited about 50% of enzyme activity over a period of 8 hours post administration.
  • the invention provides a process for the preparation of the compound of the formula ( ⁇ ) as set forth above or a salt thereof which comprises the demethylation of a compound of the formula (I) as set forth above or a salt thereof.
  • the process does not require compound of the formula (I) to be dried for the subsequent demethylation reaction, i.e. compound of the formula (I) may be wet with toluene.
  • the amount of toluene in compound of the formula (I) is in the range 1 % to 60% w/w. This is advantageous as it improves the process time and safety.
  • the process does not require the compound of the formula (II) to be slurried in EtOH. This is advantageous as it improves the process cycle-time.
  • salts thereof may be prepared, for example an alkali metal or alkaline earth metal salt, preferably the sodium or potassium salt, or a salt of a strongly basic organic compound such as a guanidine.
  • the O-demethylation reaction may be effected by reaction with a demethylating reagent.
  • a suitable demethylating reagent is a Lewis acid in the presence of appropriate base, for example, aluminium chloride (AlCh) and pyridine.
  • AlCh aluminium chloride
  • the demethylation will generally be performed at a moderately elevated temperature, preferably between 45°C-70°C, more preferably between 55 °C-65 °C.
  • the compound of the formula (II) prepared by this process can be sufficiently pure for use in a pharmaceutical composition for use in the treatment of Parkinson's disease as hereinbefore indicated.
  • the thus prepared compound of formula (II) may be ball milled or otherwise provided in microparticulate form, for example micronized through jet mills (MC JETMILL ® ).
  • MC JETMILL ® micronized through jet mills
  • a pharmaceutical composition which comprises a compound of formula (II) in microparticulate form for use in the treatment of Parkinson's disease by oral administration.
  • the product of the reaction of the compounds of formulas (IV) and (V) obtained after precipitation with ethanol may be employed without the need for isolation of crude compound of formula (III) as the workup procedure allows the isolation of compound of formula (III) with a purity not less than 95% (HPLC), preferably not less than 96% and ready to use in the next stage of the synthesis.
  • Another advantage of the present process is the optional ability to omit the isolation of any intermediate compounds of the reaction of the compounds of formulas (IV) and (V).
  • the acyl chloride may be prepared by the reaction of the compound of formula (VI):
  • reaction of compound of formula (VI) with SOCh is performed in DCM in the presence of a catalytic amount of DMF at 35-50°C, preferably at reflux temperature.
  • the compound of formula (II) in a form for use in a pharmaceutical composition may be recrystallized from propan-2-ol and formic acid and thereafter ball milled or micronized through spiral jet mills to provide particles of the desired size for good oral bioavailability and/or suitable properties (e.g. suitable particle size) for the preparation of a pharmaceutical composition.
  • FIG. 1 Process to prepare compound of formula (II) using compound of formula (I) as an intermediate according to one embodiment of the invention.
  • DMAc addition of pyridine, heat to 110°C; Quench on aq. HC1 and DCM; crystallization from DCM/EtOH; 4.
  • DCM UHP, TFAA, solvent switch from DCM to toluene/formic acid; crystallization from toluene/formic acid; 4a. Re-crystallization from formic acid/toluene; 5.
  • AICk, NMP, pyridine, the compound of formula (II) is precipitated and isolated by addition of diluted HCl; 5a. Re-crystallization from IPA/formic acid.
  • Figure 4 Process to prepare compound of formula (II) using compound of formula (I) as an intermediate according to one embodiment of the invention.
  • the present invention provides the compound of the formula (I):
  • the compound of formula (I) may be obtained in high purity, for example in crystalline form, which also helps achieve the preparation of the compound of formula (II) in highly pure forms, for example containing only very low amounts of impurities.
  • the compound of formula (I) is crystallised and/or recrystallized from a mixture of organic solvents one of which is an acid, favourably formic acid.
  • a preferred recrystallization solvent for the compound of formula (I) is a mixture of toluene and formic acid.
  • Another preferred recrystallization solvent system for the compound of formula (I) is formic acid/isopropanol (solvent/antisolvent).
  • the compound of formula (I) or salt thereof may be prepared by the oxidation of the compound of the formula (III):
  • the unsalted compound of formula (I) is prepared from a compound of formula (III) but if a salt is required this may be produced by reaction of the phenolic hydroxyl group with an appropriate base after the formation of the compound of the formula (I).
  • the oxidation reaction may be performed with any suitable oxidizing agent but preferably a peroxide is employed.
  • a peroxide may be H2O2 which is preferably employed as IkC -urea addition complex.
  • the oxidation is preferably carried out in the presence of an organic acid anhydride such as trifluoroacetic anhydride.
  • the oxidation generally takes place in a non-hydroxylic organic solvent, preferably in halogenated solvents such as methylene chloride.
  • the oxidation is preferably performed at between 15°C and 30°C, more preferably from 20°C-25°C.
  • the compound of formula (III) may be prepared by the reaction of a compound of formula (IV) wherein Y is a halo group, such as chloride, or OR in which R could be hydrogen or a C1-C6 alkyl such as methyl or ethyl:
  • the reaction of the compounds of formula (IV) and (V) can take place in an organic solvent and more generally in a mixture of organic solvents at least one of which will be basic solvent, for example pyridine.
  • a suitable mixed solvent is dimethylacetamide, tetrahydrofuran and pyridine.
  • the solvent organic mixture is a mixture of dioxane and pyridine.
  • the reaction of the compounds of formula (IV) and (V) can also take place in the presence of an organic base such as pyridine or a tertiary amine.
  • Y is OR and R is C1-C4 alkyl such as methyl
  • a Lewis acid such as aluminium trichloride, or a Bronstedt acid such as p-Toluene sulfonic acid catalyst may be required.
  • compound of formula (VIII) may be preferably used to prepare the compound of formula (III).
  • the cyclization process will take place at an elevated temperature, for example at 100°C-120°C. Particularly the process will be performed at 105°C-115°C. If desired a further organic liquid such as ethanol may be added at the end of the reaction. Suitably precipitation is not effected by the addition of such a further organic liquid.
  • this intermediate need not be isolated but becomes cyclised to the desired compound of formula (III) under the reaction conditions employed.
  • the reaction is performed at a temperature of between 100-120°C to give the desired cyclised compound of formula (III).
  • the compound of formula (V) is prepared from the compound of the formula (VII)
  • the compound of formula (IV) may be prepared from the corresponding carboxylic acid by esterification or formation of an acid chloride. Aptly for preparing an acid chloride this may involve reaction with SOCh. Such corresponding acid may be prepared by nitration of vanillic acid.
  • Compounds of Formula (IV) which are esters may also be prepared by nitration of the corresponding ester of vanillic acid, for example by nitration of the methyl ester of vanillic acid. Suitable conditions for such reactions are set forth in the Examples hereinafter.
  • the compound of formula (II) in crystalline form is particularly apt for use in pharmaceutical compositions for administration orally. In particular, such compositions may be in the form of discrete unit doses such as tablets or capsules.
  • the pharmaceutical composition which contains the compound of formula (II) in crystalline form preferably prepared as described herein, will also comprise a carrier therefor. Suitable carriers include those described in Dl, D2 or D3, referred to hereinbefore.
  • the pharmaceutical composition which contains the compound of formula (II) in crystalline form may additionally comprise levodopa (L-DOPA) and/or a peripherally selective aromatic L-amino acid decarboxylase inhibitor (AADCi).
  • the compound of formula (II) in crystalline form or pharmaceutical compositions thereof may be used to treat some central and peripheral nervous system disorders, such as Parkinson's disease, mood disorders, restless legs syndrome, gastrointestinal disturbances, edema formation states and hypertension. This may be by the administration to a patient in need thereof levodopa, a peripherally selective aromatic amino acid decarboxylase inhibitor and the crystalline compound of formula ( ⁇ ). Such administration is preferably oral administration and employs a discrete unit dose such as a tablet or capsule.
  • the crystalline compound of formula (II) employed in such compositions is preferably microparticulate, for example as formed by ball milling or by micronization through spiral jet mills. Suitable micronization may be carried out with MCJETMILL ® type 200 milling equipment.
  • the D10 (equivalent circle diameter)) is not less than 3,4,5 or 6 ⁇ (for example not less than 4 ⁇ )
  • the D50 (EDC) is 5-50, 10-45, 15-30 or 20-25 ⁇ (for example 10-45 ⁇ )
  • the D95 (EDC) is not more than 60,70,80 or 90 m (for example not more than 90 ⁇ ).
  • the D10 is not less than 4 or 5 ⁇ (for example not less than 5 ⁇ )
  • the D50 is 10-45 or 15-30 ⁇ (for example 15-30 ⁇ )
  • the D95 is not more than 60 or 70 ⁇ (for example not more than 60 ⁇ ).
  • the resulting suspension is cooled to 0-5 °C and filtered.
  • the solid was washed with acetonitrile, ethyl acetate and heptane.
  • the product was then dried under vacuum at 50 °C to yield the desired product (82 % ) .
  • Phosphoryl chloride (973.2g), tetramethylammonium chloride (67.3g) and compound of Preparation 2 (227. lg) were added to dichloromethane (500g). The suspension was heated to 85°C and stirred for 5 hours. Excess of phosphoryl chloride was removed by distillation in vacuo. The reaction mixture was cooled below 30 °C and diluted with dichloromethane. The resulting solution was added to water (1350g) at room temperature and stirred for 30 minutes. The lower organic phase was separate and the aqueous phase extracted with dichloromethane. The organic phases were combined, washed with water and then treated with charcoal. The charcoal was filtered and a solvent swap to heptane was performed by distillation at atmospheric pressure.
  • the solution was filtered at 50 °C and then cooled to 30 °C. On further cooling to 0°C crystals were obtained. These were isolated by filtration, washed twice with heptane. After drying at 50°C the desired product was obtained typically at 88-91 % .
  • Vanillic acid (75g) was suspended in acetic acid (788g). The suspension was cooled to 10°C to 15°C and nitric acid (49g or 65% solution) was added over three hours at a rate which kept temperature between 10 °C and 20 °C. The resulting yellow orange was stirred for a further one hour at 18°C to 23°C. The suspension was filtered off, washed with acetic acid, then a mixture of acetic acid and water (1/2) and then water. Yield of 53% of a 87.9% pure product was obtained.
  • the above crude product was suspended in acetic acid and warmed to 105°C to 110°C until an orange brown solution is obtained.
  • the solution was transferred to the crystallization vessel via a charcoal filter (or polish filtration) at a temperature above 85°C (optional step).
  • the solution was then cooled to 80°C to 85°C.
  • the mixture was stirred for one hour at 70°C to 80°C (optionally at 75°C) during which crystallization occurred.
  • the product suspension was cooled to 20°C to 25°C for 17 hours or stirred for at least 12h at 20 °C to 25 °C.
  • the product suspension was filtered and washed with acetic acid, then acetic acid/ water (1/2) and finally water.
  • the product was dried under vacuum at 50°C to 55°C.
  • the yield of 70% corresponds to an overall yield of 44% for both parts of this preparation.
  • the preceding crystallization step is optional and the solution may be transferred to the crystallization vessel via polish filtration instead of via a charcoal filter.
  • the post crystallization suspension may be stirred for at least 12 hours at 20° C to 25 °C as an alternative to 17 hours.
  • a reactor was charged with 525 kg of glacial acetic acid and 50 kg vanillic acid. The mixture was heated with warm water gradually to 50°C in around 75 minutes. Temperature was set to 16°C. Nitric acid, 31.4 kg was then added gradually over a period of 3 hrs. When the administration was complete the mixture was allowed to stir for additional 3.5-4.5 hours. The suspension was centrifuged whilst washed with 25 kg of acetic acid, 50 liter deionised water and 25 kg of acetic acid again. The wet crystalline material was suspended in 165 kg of acetic acid and heated at 91 °C until complete dissolution. The solution was then cooled to 19.8°C and the mixture was allowed to stir for 1 hr.
  • a suspension of vanillic acid (68.8 kg) in acetic acid (720 kg) is cooled to 17 °C before an excess of a 65% nitric acid (44.0 kg) is added. After complete dosage of nitric acid the suspension is stirred for 2 hours. The suspension is filtered off and the wet cake is successively washed with acetic acid (80.0 kg), acetic acid/water (1:2 w/w - 105 kg) and finally water (80 kg - if necessary repeat). The solid is dried at 52°C for NMT 12 hours prior going to next step. A suspension of the crude solid (650 kg) in acetic acid is warmed to 105 °C and stirred until complete dissolution of the crude solid.
  • Example la The process of Example la was scaled up to employ vanillic acid (375g) in acetic acid (3940g) to which was added nitric acid (65%, 245g) at 12°C over 3 hours followed by stirring for one hour.
  • the overall yield was 40% of a 99.9% pure product.
  • Vanillic acid methyl ester (33g) and sodium nitrite (0.625g) are charged.
  • Water (158mL) and 1,4-dioxane (158mL) are added at room temperature.
  • the reaction mixture is heated to 40 °C.
  • Nitric acid (65%) (15.75g) is added in the course of three hours and the resulting mixture is stirred for 4h after addition.
  • the reaction mixture is sampled for completion.
  • the water/nitric-acid/dioxane azeotrope is distilled off in vacuum at 40 °C.
  • the resulting product suspension is quenched by addition of sodium hydroxide solution (50% , 33.2 mL) and then stirred for 16h.
  • the quench mixture is sampled for completion.
  • Example 3c A suspension of compound of Example la (1.0 eq) in DCM (approx 3.4 vol) is treated with thionyl chloride (1.0 - 1.2 eq, for example 1.1 eq) and catalytic amount (0.011 eq) of DMF and the mixture is stirred for 16 h at 40°C. DCM is distilled off (approx 2.7 vol) and the residue is diluted with THF (approx 1.8 vol). The excess of thionylchloride is distilled off with THF/DCM and the residue after distillation is cooled to 10°C.
  • thionyl chloride 1.0 - 1.2 eq, for example 1.1 eq
  • catalytic amount 0.011 eq
  • a suspension of compound of Example la (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0 - 1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10°C.
  • the amount of DCM may be approx 3.4 as an alternative to approx 4.5 vol.
  • the catalytic amount of DMF may be about 0.011 eq as an alternative to 0.0055 eq.
  • the evaporation residue was dissolved in 36 kg dry THF.
  • the THF solution was used in
  • the dioxane/pyridine was distilled off under vacuum at 70° C. The residue was kept at 80 °C and ethanol (approx 8 vol) added to induce crystallization. The resulting yellow suspension was cooled to 0°C and stirred for two hours. The product was filtered off and washed with ethanol (2.5 vol) water (3.8 vol) and ethanol 2.5 vol). The product was dried under vacuum at 50 °C. Typical yields for this process are 82 to 85%.
  • methanol was employed in place of ethanol to induce crystallization.
  • concentrated HC1 (23.8 eq) is diluted with water (approx. 8.5 vol) and cooled to 10 °C.
  • the reaction mixture in pyridine is dosed slowly to diluted hydrochloric acid.
  • the resulting suspension is stirred for additional 2 h and the solid is filtered off.
  • the crude solid is washed once with water and pre-dried on funnel.
  • the crude solid is suspended in DCM (approx. 28.6 vol) and the suspension is heated to 40°C to reach a clear solution. Resulting solution is cooled to 20°C and extracted with water. After phase separation, the aqueous phase is re-extracted with DCM and combined organic phase are washed once with water.
  • a third reactor an emulsion of diluted hydrochloric acid (prepared from cone. HC1 (19.6 eq) and approx. 7.6 vol distilled water) and DCM (approx. 25.5 vol) is cooled to about 15 °C before the reaction mixture in pyridine is dosed slowly to the emulsion. After complete addition, the organic phase is separated and washed with water before DCM is distilled off under vacuum followed by addition of ethanol. The resulting suspension is further distilled to reduce the amount of DCM, then cooled to 5°C and stirred for additional 2 h.
  • diluted hydrochloric acid prepared from cone. HC1 (19.6 eq) and approx. 7.6 vol distilled water
  • DCM approximately 25.5 vol
  • the mixture started to reflux for 3h while the internal temperature managed to 113°C by partial distillation of some THF.
  • the reaction mixture was then cooled and introduced to a mixture of 220 kg concentrated HC1 and 170 kg of deionised water while the internal temperature was maintained between 14-16°C.
  • the reactor was rinsed with 10 kg of ⁇ , ⁇ -dimethylacetamide and 20 kg deionised water.
  • the rinse liquid was run to the mixture.
  • the suspension was then further cooled to 5-10°C and stirred for 1.5-2.0 hours.
  • the product was centrifuged and was washed 80 kg deionised water. Crude wet weight of the product was 88.6 kg.
  • the crude wet product was dissolved in 460 kg (340 L) dichloromethane at max 40°C. When dissolved the temperature was set to 20-30°C and 120 kg deionised water was added. The organic phase was separated, the inorganic phase was extracted with 80 kg dichloromethane. The organic phase of 460 kg, was then washed with 200 kg deionised water and the phases were separated. The inorganic phase was extracted with the 80 kg dichloromethane and the organic phases were unified. The organic phase obtained so was concentrated in vacuum at 35 °C to 200-240 Liter, then 260 kg ethanol 96% was continuously added and the evaporation was continued to a final 200-240 liter volume.
  • Dioxane/pyridine is distilled off. After distillation, the pit is kept at 80 °C and ethanol (1.28L, 8vol) is added at this temperature to induce crystallization. The resulting yellow suspension is cooled to 75 °C and stirred for lh at this temperature to allow crystal growth. The product suspension is then cooled to 0 °C and stirred for 2h at this temperature. The product is filtered off and washed subsequently with ethanol (400mL, 2.5vol), water (608mL, 3.8vol) and ethanol (400mL, 2.5vol). The product is dried under vacuum at 50°C until LOD is max 1% w/w.
  • the crude product was suspended in 10-12% wt/wt solution of formic acid in toluene and warmed to 90°C until dissolution of the solid.
  • the solution was cooled to 5°C and stirred at 5°C until crystallisation occurred.
  • the solid was obtained by filtration and washed with toluene. This recrystallization was repeated until the product tested as containing less than 0.1 % of starting material.
  • the pure product was dried under vacuum at 50°C.
  • Example 4b After dissolution of the product of Example 4b (24g) in DCM (388g) at 20-40 °C the yellow solution is cooled to 5°C before the temperature controlled addition of urea hydrogen peroxide complex (UHP)(17.6) and trifluoroacetic anhydride (TFAA) (37g). After addition of TFAA is complete stirring is continued for 12h at 5°C before the reaction mixture is warmed to room temperature (RT) within 1 h and stirring is continued for additional 5 h. The precipitate formed during the reaction is filtered and washed with DCM on the funnel filter. The combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure.
  • UHP urea hydrogen peroxide complex
  • TFAA trifluoroacetic anhydride
  • DCM is replaced by toluene (170g) and the resulting suspension is concentrated again under vacuum to remove surplus DCM. Distillates are replaced by fresh toluene as before and the mixture is analyzed for residual water and DCM (Residual DCM after solvent switch max. 0.5%; residual water after solvent switch max. 0.1 %).
  • Formic acid 24g is charged resulting in an approx. 10-12 %w/w formic acid in toluene solvent mixture
  • the resulting suspension is warmed to 90 °C and stirred until compete dissolution of the solid is achieved.
  • the crude product is crystallized by cooling of this solution to 5-10°C and subsequent agitation of the resulting suspension at 5-10°C.
  • the solid is filtered of washed with toluene and then dried in a stream of nitrogen gas.
  • the crude product so obtained is suspended in an approx. 10-12 %w/w solution (176g) of formic acid in toluene.
  • the suspension is warmed to 90°C and stirred until all product is dissolved.
  • crude product is isolated by filtration and subsequent washing of the wet product with toluene.
  • the precipitate formed during the reaction is filtered and the filter cake is washed with DCM.
  • the combined filtrates are diluted with DCM (325g) and then repeatedly washed with water before concentrated at atmospheric pressure.
  • DCM is replaced by toluene (170g) and the resulting suspension is concentrated again in vacuum in order to remove surplus DCM and water.
  • Distillates are replaced by fresh toluene followed by addition of formic acid (24g).
  • the resulting suspension is warmed to 80 °C and stirring is continued in order to dissolve the solid.
  • the product is crystallized by cooling of this solution to 5°C and subsequent agitation of the resulting suspension at 5°C.
  • the solid is filtered, washed with toluene and then dried in a stream of nitrogen gas.
  • the product is suspended in a formic acid / toluene (18g/158g) mixture followed by warming of the reaction mixture to 80 °C. After dissolution of the product the solution is cooled to 5°C whereby the product precipitates. After additional stirring at 5°C the suspension is filtered and the filter cake is washed with toluene. The re-crystallization of the product is repeated. The product is used as a wet material in the next process step (12. lg product obtained if dried at max. 60°C).
  • Trifluoroacetic anhydride 53 kg was administered into the reaction mixture, starting and maintaining the temperature at 6-7°C over a period of 2-3 hours. When the administration was complete the mixture was stirred for additional 30 minutes. Then the internal temperature was allowed to rise to a maximum of 25 °C over a period of 1.5 hours. The internal temperature was maintained between 20-25 °C and the mixture was allowed to react for additional 18-20 hrs. The reaction mixture was centrifuged and the fuge was washed with 45 kg dichloromethane. To the separated dichloromethane solution 460 kg (350 L) dichloromethane and 190 kg deionised water was added. The mixture was stirred for 10 minutes and the phases were separated for 30 minutes.
  • the organic phase was washed again with 2x190 kg deionised water and separated as previously. Evaporation of the unified organic solution at max 35 °C under vacuum was done to a final volume of 100-120 L. Then a total of 105 kg acetonitrile was administered into the system while the distillation was continued to keep the volume at 100-120 L. When complete an additional 170 kg (220 L) acetonitrile was added to the mixture at normal pressure. This suspension was heated to 70-80°C at normal pressure while dichloromethane was distilled off continuously. The mixture was then kept stirred for an hour. The suspension was cooled to 20-25 °C and was stirred for an additional 30 minutes.
  • the suspension was then centrifuged and was washed with 30 kg acetonitrile.
  • the wet material 29.7 kg, was vacuum dried for 16 hrs at 30°C. Dried product yield was 81.5%.
  • 27.7 kg product, 240 kg toluene and 29.2 kg formic acid was charged into reactor then heated to 90°C for complete dissolution for 1 hour. Then the solution was cooled to 7°C and then the suspension was kept at 7°C for additional 2 hrs. If necessary seeding was applied with 3-5 grams of pure product.
  • the suspension was then centrifuged for 1 hour whilst washing with 28 kg cold toluene.
  • the product was suspended in 225 kg toluene and 27.2 kg formic acid was charged.
  • the mixture then was heated to 90 °C for complete dissolution for 1 hour. Then the solution was cooled to 20-25 °C, then the suspension was kept between 15-25°C for additional 2 hrs, seeded if necessary. The suspension then was centrifuged for 60 minutes whilst washed with 28 kg cold toluene. The recrystallization process may be repeated 2-3 more times.
  • UHP - urea hydrogen peroxide HOg
  • TFAA trifluoroacetic acid anhydride
  • the biphasic system is stirred for 10 minutes at 30°C and the mixture is then allowed to separate.
  • DCM is distilled at atmospheric pressure and then replaced by toluene (1035g) applying vacuum (150mbar) and keeping internal temperature at 45°C.
  • Formic acid (300g) and toluene (900g) are added keeping the internal temperature above 40 °C.
  • the resulting solution is distilled under vacuum (150 mbar, 45°C internal temperature) until distillation ceases.
  • a suspension of crude product in formic acid (388g, 2wt) is warmed to 55°C and stirred until complete dissolution of the crude product.
  • Toluene (1242g, 6.4wt) is added maintaining the internal temperature above 50 °C.
  • the reaction is stirred at 150mBar and internal temperature 45 °C until distillation ceases.
  • the vacuum and distillation is stopped and then seed is added at 45°C.
  • the slurry is stirred for 1 hour at 45°C and cooled to 5°C in 2 hours.
  • the resulting suspension is stirred for at least 2 hours at 5°C then filtered.
  • the wet cake is washed with toluene (260g, 1.34wt). The wet cake is collected and charged into the reactor.
  • Example 5a was repeated on a larger scale employing product of Example 3 (82g), dichloromethane (1325g), urea peroxide (60. lg) and trifuoroacetic acid anhydride
  • the crude product was suspended in ethanol (492g) and warmed to reflux. The suspension was stirred for 1 hour under reflux and then cooled to room temperature. The solid was obtained by filtration, washed with ethanol and dried under vacuum at 50°C. A typical yield of 85% was achieved.
  • reaction mixture After complete conversion of the product of example 5b the reaction mixture is cooled before an aqueous diluted hydrochloric acid (water 293g, HCl 177g, 34%) is dosed.
  • aqueous diluted hydrochloric acid water 293g, HCl 177g, 34%)
  • hydrochloric acid By addition of the hydrochloric acid, crude product precipitates from the NMP/water matrix as a yellow solid which is isolated by suction filtration.
  • the resulting wet product is washed with water and 2-propanol in a replacement wash followed by drying of the wet crude product under vacuum.
  • the crude product is suspended in ethanol (282g) followed by warming of the mixture to reflux. The suspension is stirred for 1 h at reflux conditions followed by cooling to room temperature. The product is isolated by filtration of the suspension. The wet product is washed with ethanol and subsequently dried in vacuo at approx 50 °C (typically weight corrected yield was 85%).
  • the product (20g) is suspended in formic acid (725g) before the resulting suspension is warmed to max. 67 °C. Stirring is continued until complete dissolution of the product is achieved. The hot solution is filtered and the filtrate is cooled to 40 - 45° C before the product is precipitated first by concentration of the solution to approx.
  • the product may be employed in preparation of micronized material for use in pharmaceutical compositions.
  • a suspension of the product of example 5c (20g) or of example 6 (20g) in NMP (153g) is cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (8.2g) and pyridine (15.4g). After addition of pyridine is complete the reaction mixture is warmed to 60°C followed by additional 3 h reaction time. After complete conversion of the product of example 5c or of example 6 the crude product is precipitated by a temperature controlled addition of an aqueous hydrochloric acid solution (water 296g, HC1 179g, 34%). Filtration of the solid followed by washing of the wet filter cake with water and 2-propanol yields a crude product wet material which is immediately dissolved in formic acid (536g).
  • the filtrate is concentrated under vacuum followed by addition of the anti-solvent 2-propanol (318g). After aging of the resulting suspension at 55-60 °C the suspension is cooled to RT and filtered. The wet filter cake is washed with 2-propanol. The wet product is dried under vacuum at max. 58°C until LOD max. 0.5%. The yield was in the range of 70-95% If desired the product may be employed in preparation of micronized material for use in pharmaceutical compositions.
  • the reaction mixture from the demethylation was introduced into the diluted hydrochloric acid between 20-25 °C.
  • 51.2 kg dichloromethane was added to the suspension, stirred for 30 minutes and was centrifuged, washed with 60 kg deionised water and 20 kg isopropanol. Drying gave 15.9 kg of product.
  • the product was suspended in 185.3 kg of ethanol.
  • the mixture was then stirred at 78 °C for an hour, then cooled to 20-25 °C and stirred for 1 hour.
  • the suspension was then centrifuged and the filtercake was washed with 44.5 kg ethanol, 96% .
  • the solid material was dried at 50°C in vacuum in a stainless steel tray drier. 14.35 kg (90.3% yield) dry product was obtained.
  • a reactor was charged with 317.2 kg formic acid and dry product. The mixture was heated to 65 °C until all the solid dissolves. The hot solution was then filtered to an empty 1000 L reactor, was rinsed with 20 kg formic acid, then the formic acid solution was distilled partially off under vacuum to around 80-100L. 260 kg isopropanol was then introduced at 50-60 °C and stirred for 30-35 minutes. The mixture was then cooled to 20-25 °C with water in the jacket and was allowed to stir min 2 hours. The suspension was then centrifuged and was washed with 25 kg isopropanol. The wet material was removed from the fuge and was transferred into vacuum tray drier and was dried until constant weight under vacuum at 45-50°C resulting in 13.6 kg product, with a yield of 95.3% .
  • the product may be employed in preparation of micronized material for use in pharmaceutical compositions.
  • a suspension of product of Example 5e (34.1kg) in N-Methyl pyrrolidone (NMP) (182kg) is warmed to 50 °C until dissolution and then cooled to 5°C followed by a consecutive temperature controlled addition of aluminium chloride (9.8 kg) and pyridine (18.2kg). After addition of pyridine is complete the reaction mixture is warmed to 60 °C and stirred for at least 2 hours. The reaction mixture is cooled to 10-16°C (e.g. 11, 13, 15°C) before an aqueous diluted hydrochloric acid (4M solution, 283L) is dosed maintaining the temperature below 25 °C. During the addition of the hydrochloric acid the crude product is precipitated from the NMP/ water matrix as a yellow solid.
  • NMP N-Methyl pyrrolidone
  • the yellow solid is filtered and subsequently washed with water (179kg), 2-propanol (105kg).
  • the wet solid is dried under vacuum at 55 °C.
  • a suspension of wet product (25.1kg) in formic acid (813kg) is warmed to max. 67°C.
  • the mixture is stirred at 67°C until complete dissolution of the product is achieved.
  • the hot solution is filtered and the filtrate is cooled to 40 - 45 °C before the product is precipitated first by concentration of the solution to approx. 40% (v/v) of its original volume followed by addition of the anti solvent 2-propanol (380kg).
  • the resulting suspension is stirred at 55-60 °C for crystal ripening followed by cooling to RT and filtration.
  • the filter cake is washed with 2-propanol (38kg) and then dried at max. 58°C until LOD max. 0.5%).
  • the product may be milled (for example using the method of Example 8).
  • Venturi pressure range 3.0-4.0 bar; preferably the Venturi pressure is the same as the mill pressure
  • the microparticles of 5-(3-(2,5-dichloro-4,6-dimethyl-l-oxy-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]-3- nitrobenzene-l,2-diol comply with the following particle size specification (particle size determined by optical microscopy): DIO (EDC) is not less than 4 or 5 ⁇ (for example not less than 5 pm), the D50 (EDC) is 10-45 or 15-30 ⁇ (for example 15-30 ⁇ ) and the D95 (EDC) is not more than 60 or 70 ⁇ (for example not more than 60 ⁇ ).
  • Example 9 2,5-Dichloro-4,6-dimethyl-nicotinonitrile is reacted with hydroxy lamine in the presence of catalytic amounts of 1,10-phenanthroline monohydrate to yield the aldoxime (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide which represents the first coupling partner towards the synthesis of 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)- [l,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-l-nitrobenzene.
  • the second coupling partner 5-nitro-vanillic acid pure is synthesized from vanillic acid by nitration with 65 % nitric acid followed by re-crystallization of the crude 5-nitro-vanillic acid intermediate from acetic acid.
  • the convergent assembly of the oxadiazole moiety in 5-[3-(2,5- dichloro-4 , 6-dimethyl-pyr idin-3-yl)- [1 ,2,4] oxadiazol-5-yl] -2-hydroxy-3 -methoxy- 1 - nitrobenzene is achieved by first activation of 5-nitro-vanillic acid as its acid chloride and subsequent coupling with the aldoxime (Z)-2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide.
  • Oxidation of the pyridine ring to the corresponding aryl-N-oxide is achieved with trifluoroperoxoacetic acid which is formed in situ from UHP (Urea hydrogen peroxide complex) and trifluoroacetic acid anhydride.
  • the crude product is isolated by precipitation with an aqueous hydrochloric acid followed by dissolution of the precipitate in formic acid.
  • an aqueous hydrochloric acid followed by dissolution of the precipitate in formic acid.
  • partial solvent switch from formic acid to isopropanol 5-[3-(2,5-dicWoro-4,6-dimethyl-l-oxy-pyridin-3-yl)-[l ,2,4]oxadiazol-5-yl]- 3 -nitrobenzene- 1,2-diol is crystallized from the resulting formic acid/IPA crystallization matrix and finally optionally milled to the desired particle size.

Abstract

L'invention concerne un intermédiaire méthylé qui peut être déméthylé pour fournir un inhibiteur de la catéchol-O-méthyltransférase utile dans le traitement de la maladie de Parkinson. L'invention concerne également des procédés de fabrication et d'utilisation dudit intermédiaire.
EP12806720.4A 2011-12-13 2012-12-12 Composé chimique utile en tant qu'intermédiaire pour la préparation d'un inhibiteur de catéchol-o-méthyltransférase Active EP2791134B1 (fr)

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PL12806720T PL2791134T3 (pl) 2011-12-13 2012-12-12 Związek chemiczny użyteczny jako związek pośredni do wytwarzania inhibitora katechol-o-metylotransferazy
EP19194756.3A EP3604299B1 (fr) 2011-12-13 2012-12-12 Composé chimique utile en tant qu'intermédiaire pour la préparation d'un inhibiteur de transférase catéchol-0-méthyle
RS20191562A RS59666B1 (sr) 2011-12-13 2012-12-12 Hemijsko jedinjenje korisno kao intermedijer za pripremu inhibitora katehol-o-metiltransferaze
SI201231703T SI2791134T1 (sl) 2011-12-13 2012-12-12 Kemična spojina, ki je uporabna kot vmesna oblika za pripravo inhibitorja katehol-o-metiltransferaze
HRP20192133TT HRP20192133T8 (hr) 2011-12-13 2019-11-27 Kemijski spoj koristan kao posrednik za pripremu inhibitora katekol-o-metiltransferaze

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US201161570141P 2011-12-13 2011-12-13
GBGB1121413.7A GB201121413D0 (en) 2011-12-13 2011-12-13 Chemical compounds and processes
US201261593625P 2012-02-01 2012-02-01
GBGB1201758.8A GB201201758D0 (en) 2012-02-01 2012-02-01 Chemical compounds and processes
US201261718589P 2012-10-25 2012-10-25
PCT/PT2012/000048 WO2013089573A1 (fr) 2011-12-13 2012-12-12 Composé chimique utile en tant qu'intermédiaire pour la préparation d'un inhibiteur de catéchol-o-méthyltransférase

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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1907382T3 (en) 2005-07-26 2015-08-31 Bial Portela & Ca Sa Nitrocatecholderivater comt inhibitors as
EP1845097A1 (fr) 2006-04-10 2007-10-17 Portela & Ca., S.A. Derives de oxadiazole en tant qu' inhibiteurs de l'enzyme COMT
ES2597705T3 (es) 2007-01-31 2017-01-20 Bial - Portela & Ca., S.A. Derivados de nitrocatecol como inhibidores de COMT administrados con un régimen de dosificación específico
EP2276758B1 (fr) 2008-03-17 2016-01-06 Bial-Portela & CA, S.A. Formes cristallines de 5-[3-(2,5-dichloro-4,6-diméthyl-1-oxy-pyridine-3-yl)[1,2,4] oxadiazol-5-yl]-3-nitrobenzène-1,2-diol
TR201908590T4 (tr) 2009-04-01 2019-07-22 Bial Portela & Ca Sa Nitrokatekol türevlerini içeren farmasötik formülasyonlar ve bunların üretimine yönelik yöntemler.
US20140045900A1 (en) 2011-02-11 2014-02-13 Bial-Portela & Ca, S.A. Administration regime for nitrocatechols
US9126988B2 (en) * 2011-12-13 2015-09-08 Bial—Portela & Ca, S.A. Intermediate for preparing a catechol-O-methyltransferase inhibitor
WO2016083863A1 (fr) 2014-11-28 2016-06-02 Bial - Portela & Ca, S.A. Médicaments destinés au ralentissement de la progresssion de la maladie de parkinson
GB2563858A (en) * 2017-06-27 2019-01-02 Azad Pharmaceutical Ingredients Ag New route of synthesis for opicapone
WO2019123066A1 (fr) * 2017-12-18 2019-06-27 Unichem Laboratories Ltd Procédé de préparation d'opicapone et d'intermédiaires de celui-ci
CA3112994A1 (fr) 2018-10-05 2020-04-09 Neurocrine Biosciences, Inc. Procedes d'administration d'inhibiteurs de comt
WO2020072886A1 (fr) 2018-10-05 2020-04-09 Neurocrine Biosciences, Inc. Procédés d'administration d'inhibiteurs de comt
CN109529881A (zh) * 2018-11-12 2019-03-29 刘晓菊 一种治疗帕金森药物用中间体5-硝基香草酸的制备方法
JP2023517690A (ja) 2020-03-13 2023-04-26 ビアル－ポルテラ エ コンパニア，ソシエダッド アノニマ 微粉化オピカポン
GB202011709D0 (en) 2020-07-28 2020-09-09 Bial Portela & Ca Sa Solid dispersion of opicapone
GB202016425D0 (en) 2020-10-16 2020-12-02 Bial Portela & Ca Sa Treatment regimens for parkinson's disease
JP2024500754A (ja) 2020-12-17 2024-01-10 ビアル－ポルテラ エ コンパニア，ソシエダッド アノニマ 早期特発性パーキンソン病のための治療レジメン
CN112375014A (zh) * 2020-12-17 2021-02-19 重庆柳江医药科技有限公司 一种奥匹卡朋工艺杂质及制备方法和用途
WO2022180649A1 (fr) * 2021-02-26 2022-09-01 Msn Laboratories Private Limited, R&D Center Nouveau procédé de préparation de 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophényl)-1,2,4-oxadiazol-3-yl)-4,6-diméthylpyridine-1-oxide
CN113292489B (zh) * 2021-06-16 2022-08-30 泓博智源(开原)药业有限公司 二氯代二烷基烟腈的制备方法
GB202204798D0 (en) 2022-04-01 2022-05-18 Bial Portela & Ca Sa Prodrugs of opicapone
GB202212082D0 (en) 2022-08-18 2022-10-05 Bial Portela & Ca Sa Treatment regimens for parkinson's disease

Family Cites Families (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1532178A (en) 1921-07-25 1925-04-07 Louis A Godbold Lubricator
FR1260080A (fr) 1960-03-22 1961-05-05 Materiel De Forage Soc De Fab Trépan à molettes étanche
IL31990A (en) 1968-04-26 1974-05-16 Chinoin Gyogyszer Es Vegyeszet Pyridyl 1,2,4-oxadiazole derivatives,process for the preparation thereof and pharmaceutical compositions containing same
US4022901A (en) 1975-03-05 1977-05-10 E. R. Squibb & Sons, Inc. 3-Pyridinyl-5-isothiocyanophenyl oxadiazoles
US4264573A (en) 1979-05-21 1981-04-28 Rowell Laboratories, Inc. Pharmaceutical formulation for slow release via controlled surface erosion
US4386668A (en) 1980-09-19 1983-06-07 Hughes Tool Company Sealed lubricated and air cooled rock bit bearing
US5236952A (en) 1986-03-11 1993-08-17 Hoffmann-La Roche Inc. Catechol derivatives
DK175069B1 (da) 1986-03-11 2004-05-24 Hoffmann La Roche Pyrocatecholderivater
YU213587A (en) 1986-11-28 1989-06-30 Orion Yhtymae Oy Process for obtaining new pharmacologic active cateholic derivatives
DE3840954A1 (de) 1988-12-05 1990-06-07 Shell Int Research Herstellung von 2-chlornicotinsaeureestern
US5206372A (en) 1990-06-05 1993-04-27 Shell Research Limited Preparation of 2-chloropyridine derivatives
ES2066092T3 (es) 1990-11-29 1995-03-01 Wei Ming Pharmaceutical Mfg Co Coadyuvante para la formacion directa de comprimidos.
US5622976A (en) 1991-12-31 1997-04-22 Fujisawa Pharmaceutical Co., Ltd. Oxadiazole derivatives having acetylcholinesterase-inhibitory and muscarinic agonist activity
FR2730322B1 (fr) 1995-02-02 1997-04-30 Imago Monture de lunettes metallique
DE19628617A1 (de) 1996-07-16 1998-01-22 Basf Ag Direkttablettierhilfsmittel
US6206110B1 (en) 1996-09-09 2001-03-27 Smith International, Inc. Protected lubricant reservoir with pressure control for sealed bearing earth boring drill bit
WO2000017175A1 (fr) 1998-09-18 2000-03-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de p38
GB2344819A (en) 1998-12-18 2000-06-21 Portela & Ca Sa 2-Phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones
FI109453B (fi) 1999-06-30 2002-08-15 Orion Yhtymae Oyj Farmaseuttinen koostumus
CN1313465C (zh) 1999-08-19 2007-05-02 Nps药物有限公司 杂多环化合物及其用于制备代谢性谷氨酸受体拮抗剂的应用
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
FI20000635A0 (fi) 2000-03-17 2000-03-17 Orion Yhtymae Oyj COMT-inhibiittoreiden käyttö analgeettina
SE0001438D0 (sv) 2000-04-18 2000-04-18 Axon Chemicals Bv New chemical compounds and their use in therapy
DE10029201A1 (de) 2000-06-19 2001-12-20 Basf Ag Verfahren zur Herstellung fester oraler Darreichungsformen mit retardierender Wirkstoffreisetzung
GB2363792A (en) 2000-06-21 2002-01-09 Portela & Ca Sa Nitrocatechols
CN1166626C (zh) 2000-08-30 2004-09-15 李凌松 三或四取代苯基化合物、其制备方法及应用
JP2004532611A (ja) 2000-11-28 2004-10-28 ザイモジェネティクス，インコーポレイティド サイトカイン受容体ｚｃｙｔｏｒ１９
US20040097555A1 (en) 2000-12-26 2004-05-20 Shinegori Ohkawa Concomitant drugs
WO2002051442A1 (fr) 2000-12-26 2002-07-04 Takeda Chemical Industries, Ltd. Co-prescriptions
UA74419C2 (uk) 2001-02-21 2005-12-15 Ен Пі Ес Фармасьютікалс, Інк. Заміщені піридини та їх застосування як антагоністів рецептору метаботропного глутамату
EP1412327A2 (fr) 2001-05-30 2004-04-28 LG Biomedical Institute Inhibiteurs de la proteine kinase destines au traitement d'une maladie
MXPA03011196A (es) 2001-06-08 2004-10-28 Cytovia Inc 3-aril-5-aril-[1,2,4]-oxadiazoles sustituidos y analogos.
PT1408964E (pt) 2001-07-26 2007-05-31 Merck Patent Gmbh Utilização de 2-5-(4-fluorofenil) -3-piridilmetilaminometil-cromano e de seus sais fisiologicamente aceitáveis.
JP4379853B2 (ja) 2001-10-05 2009-12-09 惠民製藥股▲分▼有限公司 直接錠剤化用調合物および補助剤の調合方法
CA2509224A1 (fr) 2002-12-18 2004-07-15 Cytovia, Inc. 3,5-disubstitues-[1,2,4]-oxadiazoles et analogues servant d'activateurs des caspases et de promoteurs de l'apoptose, et leur utilisation
WO2005006945A2 (fr) 2003-07-03 2005-01-27 The Salk Institute For Biological Studies Procedes de traitement de troubles neurologiques et composes utiles a cet effet
CA2534921C (fr) 2003-08-06 2011-06-14 Vertex Pharmaceuticals Incorporated Composes d'aminotriazole utiles en tant qu'inhibiteurs des proteines kinases
DE10338174A1 (de) 2003-08-20 2005-03-24 Lts Lohmann Therapie-Systeme Ag Transdermale Arzneimittelzubereitungen mit Wirkstoffkombinationen zur Behandlung der Parkinson-Krankheit
US7300406B2 (en) 2003-09-30 2007-11-27 Carter Vandette B Medical examination apparatus
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
WO2005105780A2 (fr) 2004-04-28 2005-11-10 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de la rock et d'autres proteines kinases
GB0510143D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds A1
WO2006051154A1 (fr) 2004-11-10 2006-05-18 Orion Corporation Traitement du syndrome des jambes sans repos
WO2006061697A1 (fr) 2004-12-06 2006-06-15 Themis Laboratories Private Limited Compositions de sulfonyluree et procede de preparation de ces dernieres
US20080051441A1 (en) 2004-12-28 2008-02-28 Astrazeneca Ab Aryl Sulphonamide Modulators
WO2006071184A1 (fr) 2004-12-28 2006-07-06 Astrazeneca Ab Modulateurs de type arylsulfonamide
ATE477253T1 (de) 2005-04-26 2010-08-15 Neurosearch As Neuartige oxadiazol-derivate und deren medizinische verwendung
US20060257473A1 (en) 2005-05-11 2006-11-16 Porranee Puranajoti Extended release tablet
GB0510139D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B1
EP1888523B1 (fr) 2005-06-03 2011-10-26 Abbott Laboratories Derives de cyclobutyl amine
JP2007024970A (ja) 2005-07-12 2007-02-01 Miyakawa:Kk 液晶表示装置の開口効率を上昇させるための樹脂レンズ製造法及びその製造装置
US20090000437A1 (en) 2005-07-14 2009-01-01 Provo Craft And Novelty, Inc. Methods for Cutting
DK1907382T3 (en) 2005-07-26 2015-08-31 Bial Portela & Ca Sa Nitrocatecholderivater comt inhibitors as
FR2889525A1 (fr) 2005-08-04 2007-02-09 Palumed Sa Nouveaux derives de polyquinoleines et leur utilisation therapeutique.
US20070048384A1 (en) 2005-08-26 2007-03-01 Joerg Rosenberg Pharmaceutical compositions
WO2007061862A2 (fr) 2005-11-18 2007-05-31 Janssen Pharmaceutica N.V. 2-ceto-oxazoles en tant que modulateurs d'amide d'acide gras hydrolase
JP4738419B2 (ja) 2005-11-30 2011-08-03 富士フイルムＲｉファーマ株式会社 アミロイドの凝集及び／又は沈着に起因する疾患の診断薬及び治療薬
GB0606774D0 (en) 2006-04-03 2006-05-10 Novartis Ag Organic compounds
EP1845097A1 (fr) * 2006-04-10 2007-10-17 Portela & Ca., S.A. Derives de oxadiazole en tant qu' inhibiteurs de l'enzyme COMT
PE20080906A1 (es) 2006-08-17 2008-07-05 Kemia Inc Derivados heteroarilo como inhibidores de citocina
US8486979B2 (en) 2006-12-12 2013-07-16 Abbvie Inc. 1,2,4 oxadiazole compounds and methods of use thereof
US20080167286A1 (en) 2006-12-12 2008-07-10 Abbott Laboratories Pharmaceutical compositions and their methods of use
ES2597705T3 (es) * 2007-01-31 2017-01-20 Bial - Portela & Ca., S.A. Derivados de nitrocatecol como inhibidores de COMT administrados con un régimen de dosificación específico
MX2010002258A (es) 2007-08-27 2010-04-22 Helicon Therapeutics Inc Compuestos terapeuticos de isoxazol.
US20110014282A1 (en) 2008-02-28 2011-01-20 De Vasconcelos Teofilo Cardoso Pharmaceutical composition for poorly soluble drugs
EP2276758B1 (fr) 2008-03-17 2016-01-06 Bial-Portela & CA, S.A. Formes cristallines de 5-[3-(2,5-dichloro-4,6-diméthyl-1-oxy-pyridine-3-yl)[1,2,4] oxadiazol-5-yl]-3-nitrobenzène-1,2-diol
WO2010014025A1 (fr) 2008-07-29 2010-02-04 Bial - Portela & Ca., S.A. Régime d'administration de nitrocathéchols
TR201908590T4 (tr) 2009-04-01 2019-07-22 Bial Portela & Ca Sa Nitrokatekol türevlerini içeren farmasötik formülasyonlar ve bunların üretimine yönelik yöntemler.
PT2413913T (pt) 2009-04-01 2022-06-09 Bial Portela & Ca Sa Formulações farmacêuticas que compreendem derivados de nitrocatecol e métodos para os preparar
KR101868326B1 (ko) 2010-03-04 2018-06-19 오리온 코포레이션 파킨슨병의 치료를 위한 레보도파, 카르비도파 및 엔타카폰의 용도
US20140045900A1 (en) 2011-02-11 2014-02-13 Bial-Portela & Ca, S.A. Administration regime for nitrocatechols
US9126988B2 (en) * 2011-12-13 2015-09-08 Bial—Portela & Ca, S.A. Intermediate for preparing a catechol-O-methyltransferase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2013089573A1 *

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ES2758659T3 (es) 2020-05-06
US9630955B2 (en) 2017-04-25
JP2020059729A (ja) 2020-04-16
SI2791134T1 (sl) 2020-01-31
US9126988B2 (en) 2015-09-08
HRP20192133T8 (hr) 2021-02-19
CA2858025A1 (fr) 2013-06-20
PL2791134T3 (pl) 2020-03-31
JP2015500335A (ja) 2015-01-05
JP2018052949A (ja) 2018-04-05
EP3604299B1 (fr) 2023-07-26
CA3088684C (fr) 2021-10-26
HRP20192133T1 (hr) 2020-02-21
RS59666B1 (sr) 2020-01-31
ES2960805T3 (es) 2024-03-06
EP2791134B1 (fr) 2019-09-25
CA3088684A1 (fr) 2013-06-20
WO2013089573A1 (fr) 2013-06-20
PT3604299T (pt) 2023-10-31
BR112014014341A2 (pt) 2017-08-22
CY1122580T1 (el) 2021-01-27
DK2791134T3 (da) 2019-12-09
US20140350057A1 (en) 2014-11-27
EP3604299A1 (fr) 2020-02-05
CA2858025C (fr) 2020-09-22
JP6456143B2 (ja) 2019-01-23
US20160009700A1 (en) 2016-01-14
HUE047856T2 (hu) 2020-05-28
PT2791134T (pt) 2019-12-18
JP6721558B2 (ja) 2020-07-15

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